Department of Immunology and Inflammation Drug Discovery, Bristol-Myers Squibb, Princeton, NJ 08543, USA.
J Immunol. 2010 Apr 1;184(7):3917-26. doi: 10.4049/jimmunol.0901095. Epub 2010 Feb 26.
LFA-1 appears to play a central role in normal immune responses to foreign Ags. In autoimmune or inflammatory diseases, there is increased expression of LFA-1 and/or its counterligand, ICAM-1. Others have demonstrated that the targeted disruption of LFA-1:ICAM interactions, either by gene deletion or Ab treatment in mice, results in reduced leukocyte trafficking, inflammatory responses, and inhibition of inflammatory arthritis in the K/BxN serum transfer model. However, there has been little success in finding a small-molecule LFA-1 antagonist that can similarly impact rodent models of arthritis. In this paper, we present the first reported example of an LFA-1 small-molecule antagonist, BMS-587101, that is efficacious in preclinical disease models. In vitro, BMS-587101 inhibited LFA-1-mediated adhesion of T cells to endothelial cells, T cell proliferation, and Th1 cytokine production. Because BMS-587101 exhibits in vitro potency, cross-reactivity, and oral bioavailability in rodents, we evaluated the impact of oral administration of this compound in two different models of arthritis: Ab-induced arthritis and collagen-induced arthritis. Significant impact of BMS-587101 on clinical score in both models was observed, with inhibition comparable or better than anti-mouse LFA-1 Ab. In addition, BMS-587101 significantly reduced cytokine mRNA levels in the joints of Ab-induced arthritis animals as compared with those receiving vehicle alone. In paws taken from the collagen-induced arthritis study, the bones of vehicle-treated mice had extensive inflammation and bone destruction, whereas treatment with BMS-587101 resulted in marked protection. These findings support the potential use of an LFA-1 small-molecule antagonist in rheumatoid arthritis, with the capacity for disease modification.
LFA-1 似乎在对外来抗原的正常免疫反应中发挥核心作用。在自身免疫或炎症性疾病中，LFA-1 及其配体 ICAM-1 的表达增加。其他人已经证明，通过基因缺失或在小鼠中使用抗体治疗来靶向破坏 LFA-1:ICAM 相互作用，可导致白细胞迁移、炎症反应减少，并抑制 K/BxN 血清转移模型中的炎症性关节炎。然而，在寻找能够类似地影响关节炎啮齿动物模型的小分子 LFA-1 拮抗剂方面，几乎没有成功。在本文中，我们提出了第一个报道的 LFA-1 小分子拮抗剂 BMS-587101 的实例，该拮抗剂在临床前疾病模型中有效。在体外，BMS-587101 抑制了 LFA-1 介导的 T 细胞与内皮细胞的黏附、T 细胞增殖和 Th1 细胞因子的产生。由于 BMS-587101 在体外具有效力、交叉反应性和啮齿动物中的口服生物利用度，我们评估了在两种不同的关节炎模型中口服该化合物的影响：抗体诱导的关节炎和胶原诱导的关节炎。在两种模型中，BMS-587101 对临床评分均有显著影响，其抑制作用与抗小鼠 LFA-1 抗体相当或更好。此外，与单独接受载体的动物相比，BMS-587101 显著降低了抗体诱导的关节炎动物关节中的细胞因子 mRNA 水平。在胶原诱导的关节炎研究中取自爪子，接受载体治疗的小鼠的骨头有广泛的炎症和骨破坏，而用 BMS-587101 治疗则有明显的保护作用。这些发现支持在类风湿关节炎中使用 LFA-1 小分子拮抗剂，具有疾病修饰的潜力。
